Process for the preparation of steroidal ethers and thioethers



United States Patent 3,193,563 PRGCESS FOR THE PREPARATION OF STEROIDAL E'HERS AND THIOETHERS Alexander D. Cross, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed May 24, 1963, Ser. No. 282,848 13 Claims. (Cl; 260-397) This invention relates to a novel process for the preparation of cyclopentanopolyhydrophenanthrene derivatives, as well as to said cyclopentanopolyhydrophenanthrene derivatives themselves.

vMore particularly, this invention relates to a novel process for the preparation of the corresponding steroidal ethers and thioethers from ketals, monothioketals and dithioketals (mercaptols) of keto derivatives of the androstane, estrane, pregnane and 19-norpregnane series, and preferably fromsuch keto derivatives wherein the ketal, monothioketals and dithioketal groups are present at one or more of positions 3, 17 and 20, or from acetals, monothioacetals and dithioacetals (mercaptals) of aldehyde derivatives of the androstane, estrane, pregnane and 19-norpregnane series, and preferably from such aldehyde derivatives wherein the acetal, monothioacetal and dithioacetal groups are at the 19-position.

The process of the present invention can be illustrated by the following reaction sequences:

In the above Formulas I-lV, Z represents a secondary carbon atom in a steroid of the androstane, estrane, pregnane or 19-norpregnane series, especially a carbon atom at the 3, 17 or -position, to which a ketonic oxygen had been attached prior to the formation of a ketal, monothioketal or dithioketal derivative thereof; Z represents a primary carbon atom in a steroid of the androstane, estrane, pregnane or 19-norpregnane series, especially a carbon atom at the l9-position, to which an aldehydic oxygen had been attached prior to the formation of an acetal, monothioacetal or dithioacetal derivative thereof; X and Y each represent either oxygen or sulfur; R and R when taken separately, each represent a hydrocarbon residue of up to 10 carbon atoms, while R and R taken together represent a hydrocarbon residue containing from 2 to 10 carbon atoms, inclusive, and R represents a hydrocarbon residue of up to 10 carbon atoms (1 a hydroxyhydrocarbon or mercaptohydrocarbon residue containing from 2 to 10 carbon atoms, inclusive.

The hydrocarbon residues represented by R and R can be aliphatic, including saturated or unsaturated straight and branched chain aliphatic, cyclo-aliphatic, including saturated or unsaturated cycloaliphatic, or aromatic, including aryl, alkaryl and aralkyl. Furthermore, when the steroidal ketal, monothioketal, dithioketal, acetal, monothioacetal or dithioacetal starting material is formed using a monohydric alcohol or thiol, these hydrocarbon residues will be monovalent radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, octyl, decyl, cyclohexyl, methylcyclohexyl, cyclohexenyl, benzyl, and the like. Similarly, when the steroid starting material is formed using a dihydric alcohol, a

dithiool or a monothioglycol, these hydrocarbon residues will be divalent residues, such as ethylene, i.e.,

--CH -CH propylene, butylene, but-l-enylene, but-l-inylene, 2-methylbutylene, 2,3-din1ethylbutylene, Z-methylbut-Z-enylene, 2,3-dimethylbut 2 enylene, 2,3-dimethylpentylene, 2,3- dimethylpent-Z-enylene, hexamethylene, octamethylene, isooctalene, 2,3-dirnethylheptalene, 2-methyl-3-ethylheptalene, isooct-Z-enylene, 2,3-dimethylhept-2-enylene, Z-meth- I yl-3-ethylhept-Z-enylene, and the like.

The monovalent hydrocarbon residues represented by R being derived from a hydrocarbon residue represented by R R or R and R taken together, can also be aliphatic, cycloaliphatic or aromatic. However, the hydrocarbon residues represented by R can also contain a hydroxyl or a mercapto group. Thus, in addition to the monovalent hydrocarbon residues set forth hereinabove for R and R and, in the case of the aforementioned divalent hydrocarbon residues represented by R and R taken together, their monovalent counterparts, e.g., Z-methylbutyl rather than 2-methylbutylene, R can also represent groups such as B-hydroxyethyl, fl-mercaptoethyl, 3-hydroxyhex-2-yl, 6-hydroxyhexyl, 6-mercaptohexyl, and the like.

As previously indicated, the steroid starting materials used in practicing the present invention are ketals, monothioketals and dithioketals of keto derivatives, and acetals, monothioacetals and dithioacetals of aldehyde derivatives, of the androstane, estrane, pregnane and 19-norpregnane series. Although starting materials having ketal, monothioketal or dithioketal groups at one or more of positions 3, l7 and 20, or acetal, monothioacetal or dithioacetal groups at position 19 are preferred, starting materials having such groups at any position on the steroid nucleus, e.g., ketal groups and the like at the 11-, 15- or l6-position or acetal groups and the like at the 2-, 17- or 18-position, can be employed. Similarly, a wide variety of other noninterfering substituents can also be present on the steroid nucleus and, therefore, in the final products, e.g., at the 2-, 4-, 6-, 7-, 9-, 11-, 12-, 14-, 15-, 16- and 21-positions. Thus, for example, hydroxyl groups can be present at the 2-, 4-, 6-, 9-, 11-, 12-, 14-, 15-, 16- and 21-positions, alkyl groups at 2-, 4-, 6-, 7-, 9-, 11-, 12- or 16-position, and so on. It should be noted that positions and substituents just mentioned are intended to be illustrative rather than restrictive.

The starting materials employed in practicing the present invention are prepared by conventional procedures, involving reaction of the corresponding steroidal ketones and aldehydes with a monohydric alcohol, such as methanol, ethanol, propanol, t-butanol, hexanol, cyclohexanol, octanol, benzyl alcohol, and the like, a dihydric alcohol, such as ethylene glycol, propylene glycol-1,2, propylene glycol-1,3, butanediol-l,3, butanediol-1,4, hexanediol- 1,6, hexanediol-2,3, heptamethylene glycol, octamethylene glycol, and the like, a thiol, such as ethanethiol, propanethiol, l-butanethiol, and the like, a dithiol, such as ethanedithiol-1,2, prapanedithiol-1,3, butanedithiol-1,3, and the like, or a monothioglycol, such as ,B-mercaptoethanol, 'ymercaptopropanol, l-mercaptopropanol-Z, fi-mercaptobutanol, anl the like, in the presence of an acid, such as ptoluenesulfonic acid and the like.

In accordance with the present invention there may be readily prepared a number of useful steroid ethers and thioethers which are produced only with great difiiculty by other methods. Examples of compounds which may be easily produced by the process of the present invention are: 17p-(cyclohexyloxy)-3fi-hydroxy-androstane, which has a favorable anabolic-androgenic ratio with very few undesirable side effects, 17,8-(6'-hydroxyhexyloxy)-3- hydroxy-N' -estratriene, 17(3- (2'-hydroxyethylthio -3- hydro'xy-M-pregnene hydroxy A -estratriene, 175 (2' mercaptoethylthio)-3-hydroxy-A -estriatriene, 1713-(2 hydroxyethoxy)-3-methoxy-A -estratriene and 2OB-(2-hydroxyethoxy)-3[3-hydroxy-A pregnene, all of which are of great utility in lowering the cholesterol level in the blood, 3,8, 175, 19-tri(2-hydroxyethoxy)-A -andrstene, which is useful in the treatment of premenstrual tension, suppresses the output of the pituitary gland and lowers the blood cholesterol level.

The conversion of the aforementioned steroidal ketals, monothioketals, dithioketals, acetals, monothioacetals and dithioacetals to the corresponding steroidal ethersand thioethers is accomplished through the use of a cleaving agent which imay be any of:

(l) A hydride of an element of'subgroup III-A of the Periodic Chart, such as boron hydride (or diborane and the like), aluminum hydride, and the like; i

(2) A hydride of an element of subgroup III-A of the Periodic Chart together with a Lewis acid free from active hydrogen containing an element having an atomic.

number of 26'to 28 inclusive or an element of subgroup III-A of the Periodic Chart, such as ferric chloride, boron trifiuoride, boron trichcloride, aluminum fluoride, aluminum chloride, aluminum bromide, gallium chloride, and the like; a

(3) A hydride of an element of subgroup III-A of the Periodic Chart together with a hydrogen halide, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, and the like; v V I v (4) An alkali metal hydride, such as lithium hydride, sodium hydride, potassium hydride, and the like, together with a Lewis acid free from active hydrogen containing an element of subgroup III-A of the Periodic Chart, such as boron trifluoride, aluminum trichloride, boron trichloride and the like; a v

* (5) An alkaline earth metal hydride, such as magnesium hydride, calcium hydride, and the like, together with aLewis acid free from active hydrogen containing an element of subgroup III-A of the Periodic Chart, such as boronv trifiuoride, boron trichloride, aluminumtrichloride and the like;

-' (6) A double. metal hydride containing at least one element'of subgroup III-A of the Periodic Chart, such as lithium aluminum hydride, potassium aluminum hydride, magnesium aluminum hydride, lithium gallium hydride, zinc aluminum hydride, sodium borohydride, potassium borohydride, aluminum borohydride, and. the like, to-

gether with a Lewis acid free from active hydrogen containing an element having an atomic number of 26 to 28 inclusive or an element of subgroup III-A of the Periodic Chart, such as boron trichloride, boron trifluoride, aluminum trichloride and the like;

(7) A double metal hydride, containing at least one element of subgroup III-A of the Periodic Chart, together with a hydrogen halide.

In practicing the process of the present invention, a compound represented by Formula I or II is treated with a cleaving agent described above in an organic solvent free from active hydrogen, preferably comprising an ether function, such as ethyl ether, tetrahydrofuran, dioxane etc., thus affording the corresponding ether or thioether represented by Formula III or IV.

When the starting compound is a cyclic monothio (ketal or acetal), the reductive cleavage occurs on the oxygen linkage, thus affording a thioether with an hydroxyl substituent. For example, 17-cycloethylenedioxy-3-hydroxy- A -estratriene afiords 17B-(2'-hydroxyethoxy)-3-hydroxy-A -estratriene.

When the starting compound is a cyclic dithio(ketal or acetal) the final compound is a thioether with a mercapto substituent. For instance, 20-(cycloethylenedithio)3,B-

furnishes 20,8-(2'-mercaptoethylthio)-3fl-hydroxy-A -pregnene.

' It is known to those skilled in the art that ketone or aldehyde groups present as suchon the molecule of the 4 starting compound, are reduced to the corresponding alcohols under the conditions of the present process.

The conditions at which the process of the present invention may be carried out have no critical importance and may be changed within wide ranges. For example, the temperature may vary from approximately ambient to the reflux temperature of the reaction mixture; the time may be from about 30 minutes to about 24 hours, thus having only an influence on the yield of final product ,but not on its nature. The amount of reagent of the type described above with respect to the steroid reactant, may range from approximately 0.25 molar equivalent of each ingredient, to large excesses, the latter being preferred for better yields in final compound. The ratio of one ingredient with respect to the other, e.g., the metal hydride with respect to. the Lewis acidor hydrogen halide must not necessarily be constant and may vary from approximately 1:1 to large excesses of Lewis acid or hydrogen halide.

Similarly, the isolation of the final product has no critical importance and may be effected by conventional procedures.

The following specific examples serve to illustrate but 7 are not intended to limit the scope of the present invention.

Example I A mixture of 5 g.- of estrone, 150 cc. of anhydrous .benzene, 60 cc. of ethyleneglycol distilled over sodium .hydroxide and- 800 mg. of ,p-toluenesulfonic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate vand evaporated to dryness. The residue crystallized from acetone-hexane to give 17- cycloethylenedioxy-3-hydroxy-A 'W -estratriene (Cpd. No. 1).

The starting compounds listed hereinafter under A, were treated following the same procedure, thus affording the corresponding products set forth below, under B.

A Cpd. B No.

Estrone methyl ether 2 17-cycloethylenedioxy-3- methoxyA )-estratrlenc. Dihydrotestosterone 3 B-cycloethylenedioxy-Hflhydroxy-androstane. Testosterone 4 3-cycloethylenedioxy-17flhydroxy-A -androstene. 17a-methyl-dehydro-testos- 5 3-cycloethylenedioxy-17flteronc hydroxy-17a-methylandrostane. Pregnenolone 6 20-cycloethylene dioxy-3flhydroxy-A -pregnene. Progesterone 7 3,20-biscycloethylenedioxy- A -pregnene. 19-nor-d hydro-testosterone 8 B-eycloethylenedioxy-Uflhydroxy-estrane. 19nor-pregnenolone 9 20-eycloethylenedioxy-3B- hydroxydQ-nor-M-pregnene. Allopregnane-3,20-dl0ne 10 3,20-biscycloethylenedioxyallopre gnane Androstan-ZiB-ol-H-one 11 17-cycloethylenedioxy-3B- V hydroxy-androstane. A -pregnen-19-al-3,20 drone 12 3,19,20-tricyc1oethylenedioxy-A -pregnene. N-androsten-l9-al-3,17-d one l3 3,17,19-tricyeloethylenedioxy-N-androstene. lfia-rnethyl-progesterone 14 3,ZO-biscycloethylenedloxylfia-methyl-A -pregnene.

Example 11 ethyleneglycol was substituted by hexam'ethylene glycol Estrone was treated in accordance with Example I, except that ethylene glycol was'substituted'by 2,3-hexanediol.

5 thus yielding 17-(hexane-2',3-dioxy)-3-hydroxy-A estratriene (Cpd. No. 17).

Pregnenolone was treated by the same procedure, thus yielding 2O-(hexane-2',3'-dioxy)-3e-hydroxy-A -pregnene- (Cpd. No.18).

Example IV Estrone was treated following the procedure described in Example I, except that ethanol was used instead of ethyleneglycol, thus yielding 17,l7-(diethoxy)-3-hydroxy- A -estratriene (Cpd. No. 19).

Androstan-3B-ol-17-one was treated by the above procedure thus furnishing 17,17-(diethoxy)-3B-hydroxyandrostane (Cpd. No. 20).

Example V Estrone was treated according to Example I, except that ethyleneglycol was substituted by propanol, thus giving 17,17 (dipropoxy) B-hydroxy-A -estratriene (Cpd. No. 21).

Allopregnane-3,20-dione was treated by the same procedure, thus yielding 3,3,20,ZO-tetrapropoxy-allopregnane (Cpd. No. 22).

Example VI Estrone was treated according to Example I, except that ethyleneglycol was substituted by terbutanol thus yielding 17,17-(diterbutanol)-3-hydroxy-A estratriene (Cpd. No. 23).

Dihydrotestosterone was treated by the same procedure, thus giving 3,3-(diterbutoxy)-17/i-hydroxy-androstane (Cpd. No. 24).

Example VII Upon treatment of esterone by the procedure described in Example I, except that ethylene glycol was substituted by fl-mercaptoethanol, there was produced 17(cycloethylenethioxy)-3-hydroxy A estratriene (Cpd. No. 25).

Androstan-3fl-ol-17-one was treated by the same pro cedure to give 17-(cycloethylenethioxy)-3,B-hydroxyandrostane (Cpd. No. 26).

Example VIII When treating estrone by the procedure of Example I, except that ethylene glycol Was substituted by 1,2-ethanedithiol, there was produced 17- (cycloethylenedithio)-3- hydroxy-A -estratriene (Cpd. No. 27).

Prenenolone was treated by the latter procedure to give 20-(cycloethylenedithio)-3[i-hydroxy A pregnene (Cpd. No. 28).

Example IX Estrone was treated according to Example I, except that ethylene glycol was substituted by ethanethiol, thus yielding 17 17 diethylthio -3-hydroxy-A -estratriene (Cpd. No. 29).

Allpregnane-3,20-dione was treated by the same procedure, thus furnishing 3,3;20,-2()-tetraethylthioallopregnane (Cpd. No. 30).

Example X A slow stream of diborane mixed with boron trifluoride was passed through a solution of 17-cycloethylenedioxy-3- hydroxy-A -estratriene (Cpd. No. 1) in 125 cc. of tetrahydrofuran for hours. The excess of diborane was decomposed by careful addition of water. Then 1 It. of Water Was added and the formed precipitate was filtered, washed and dried, thus giving 9.6 g. of organoboron compound.

This material was dissolved in 200 cc. of tetrahydrofuran and treated with 9 g. of sodium hydroxide previously dissolved in 25 cc. of water, and 45 cc. of 35% hydrogen peroxide, stirring and keeping the temperature around 15 C. The mixture was stirred for 2 hours, then the precipitated product was filtered, washed, dried and chromatographed on alumina thus producing l7fl-(2'-hy- 'drofuran. 'cooled and cautiously treated with 5 cc. of ethyl acetate 6 droxy ethoxy)-3-hydroxy-A -estratriene (Cpd. No. 31).

The compounds Nos. 2 and 3 were treated by the same procedure thus yielding respectively: 17B-(2-hydroxy ethoxy)-3-methoxy-A -estratriene (Cpd. No. 32), and 3fi-(2'-hydroxy ethoxy)-17fi hydroxy androstane (Cpd. No. 33).

Example XI The Compounds Nos. 15, 16, 17, 19, 20, 21, 22, 25, 27 and 30 were treated according to the procedure described in Example X, thus furnishing respectively:

Cpd. No.

34. 17,8-('6'-hydroxyhexyloxy)-3-hydroxy-A estratriene,

35. 3 B-(6'-hydroxyhexyloxy)-17,8-hydroxyandrostane,

36. 17/3-(3'-hydroxyhexyl-2'-oxy-3-hydroxy- A -estratriene,

37. 17fi-ethoxy-3hydroxy-A -estratriene,

38. 17B-ethoxy-313-hydroxy-androstane,

39. 17,8-propoxy-3hydroxy-A -estratriene,

40. 3,8,20 3-dipropoxy-allopregnane,

41. 17,8-(2-hydroxyethylthio)-3-hydroxy-A estratriene,

42. 17/8-(2'-mercaptoethylthio)-3-hydroxya r -estratriene,

43. 3,8,20fi-diethylthio-allopregnane.

Example XII A solution of 1 g. of 17-cycloethylenedioxy-3-hydroxy- A -estratriene (Cpd. No. 1), in 50 cc. of tetrahydrofuran was added over a 30 minutes period to a stirred suspension of 1 g. of lithium aluminum hydride and 6 g. of aluminum trichloride in 50 cc. of anhydrous tetrahy- The mixture was refiuxed for 2 hours, then and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization from acetone-hexane thus giving 17fl-(2'-hydroxy ethoxy)-3-hydroxy-A -estratriene, which was identical with Compound No. 31, obtained according to Example X.

Example XIII gave 17B-(2-hydroxy ethoxy)-3-hydroxy-A eestratriene (Cpd. No. 31).

Example XIV A solution of l g. of Compound N0. 1 in 50 cc. of anhydrous tetrahydrofuran was added to a stirred suspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran then there was passed a stream dry hydrogen chloride during 3 hours with constant stirring at room temperature. The resulting mixture was cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. After 5 minutes there were further added cc. of ethyl acetate, the resulting mixture was washed successively with water, dilute aqueous sodium bicarbonate solution and water to neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the residue from acetone-hexane yielded a product identical with 17B-(2'-hydroxy ethoxy) 3 hydroxy- A -estratriene (Cpd. No. 31).

of boron trifluoride, thus with Cpd. No. 31.

7 Example X V The Compound No. 1 was treated according to Example XII except that lithium aluminum hydride and aluminum a product identical with Compound No. 31.

Example XVI The Compound No. 1 was treated according to Example XIII except that aluminum tribromide and sodium borohydride were respectively substituted by ferric trichloride and potassium borohydride, thus yielding a product identical with Compound No. 31.

' Example XVII Example XVIII 7 Upon treating Compound No. 1 by the procedure described in Example XIII, but using aluminum borohydride instead of sodium borohydride, there was obtained a product identical with Compound No. 31.

Example XIX The Compound No. 1 was treated following the procedure described in Example X, except that gaseous boron trifluoride was substituted by boron trichloride dissolved in the reaction mixture, thus yielding. exactly the same compound as in said example.

Example XX The Compound No. 1 was treated in accordance with Example XIV, except that hydrogen chloride was substituted by hydrogen bromide, thus producing the same compound as in said example. 5

Example XXI The Compound No. 1 was treated according to Example XIV, but hydrogen fluoride was used instead of hydrogen chloride, to give a product identical with Compound Example XXII Example XXIII The procedure of Example XXII was repeated, except that it was carried out without hydrogen chloride thus yielding a product identical with Compound No. 31.

V 7 Example XXIII V The procedure described in Example X was repeated except that boron trifluoride was substituted by hydrogen fluoride, thus giving identical results.

Example XX The Compound No. 1 was treated according to-Example X except that the reaction was carried out in the absence yielding a compound identical Example XX VI The Compound No. 1 was treated following the procedure described in Example'X, except that gaseous boron :trifluoride was substituted by aluminum trifluoride sus- Example XX VII trichloride, were respectively substituted by magnesium aluminum hydride and aluminum trifluoride thus yielding V '8 minum trichloride were respectively substituted by-lithium gallium hydride and gallium trichloride, thus yielding a .product identical with Compound N0. 31.

. Example XXI III A solution of 1 g..of Compound No.3 in 50 cc. of tetrahydrofuran was added over a 30 minute period to 'a stirred solution containing 1 g. of aluminum hydride 'in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water.- Solid 7 sodium sulfate was added, the inorganic material filtered The Compound No. 1 was treated according to Exam- 7 ple XII, except that lithium aluminum hydride and alu- Example XXIX The Compounds Nos. 2 to 14, inclusive, were treated according to Example XII, thus yielding respectively:

Cpd. No.- v

44. 17,8-(2-hydroxy ethoxy)-3-methoxy-A estratriene.

45. 3 B-(2-hydroxy ethoxy)-l7/3-hyd-roxy-androstane.

46. 3B-(2-hydroxy ethoxy)-l7p-hydroxy-A -andros- -tene.

47. 3fi-(2'-hydroxy ethoxy)-17;8-hydroxy-17amethyl-androstane.

48. ZOfi-(T-hydroxy ethoxy)-3[3-hydroxy-A -preg- 'nene.

49. 3,9,20B-bis-(2'-hydroxy ethoxy)-A -pregnene.

51. 20fl-(2'-hydroxy ethoxy)-3p-hydroxy-19-nor-A pregnene. 52. 3B,20,8-bis-(2'-hydroxy ethoxy)-a1lopregnane. 53. l7,6-(2'-hydroxy ethoxy)-3/3-hydroxy-androstane.

54. 3,8,l9,20fitri-(2'-hydroxy ethoxy)A -pregnene. 55. 35,175,19-tri-(2'-hydroxy ethoxy)-A -androstene. 56. 3 3,2OB-bis-(2'-hydroxy-ethoxy)-l6a-methyl A pregnene.

Example XXX The Compounds Nos. 15 to 30, inclusive, were treated according to Example XII, thus furnishing respectively:

Cpd. No.

5 7. 6-hydroxyhexyloxy) -3 -hydroxy-A z estratriene (identical with Cpd. No. 34),

58. 3 5- 6'-hydroxyhexyloxy) -17;3hydroxy-androstane (identical with Cpd. 'No. 35), 59. 17,3-(3-hydroxyhexyl-2'-oxy)-3-hydroxy- A estratriene (identical with Cpd. No. 36), 60. 20;3-(3'-hydroxyhexyl-2'-oxy)-3fl-hydroxy-A pregnene, 61. 17,8-ethoxy-3fl-hydroxy-A -estratriene (identical with Cpd. No. 37), 62. 17/3-ethoxy-3fl-hydroxy-androstane (identical with Cpd. No. 38), I 63. 17,8-propoxy-3-hydroxy-A -estratriene (identical with Cpd. No. 39), Y 64. 35,20,8-dipropoxy-allopregnane (identical with Cpd. No. 40), 65. 17/3-terbutoxy-3-hydroxy-A -estratriene, V 66. 3 S-terbutoxy-l7l3-hydroxy-androstane,

, 67. 17B-(2-hydroxyethylthio)-3-hydroxy-A estratriene (identical with Cpd; No. 41), I 68. 17B-(2'-hydroxyethylthio)-3,B-hydroxy-androstane, 69. 17B:(2'-mercaptoethylthio)-3-hydroxy-A estratriene (identical with Cpd. No. 42), 70. 20/3 (2'-mercaptoethylthio)-3B-hydroxy-A pregnene, I 7 1. 17 ,B-ethylthio-3-hydroxy-A -estratriene, 72. 3,620p-diethylthio-allopregnane (identical with Cpd. No. 43). a

9 Example XXXI The Compound No. l was treated according to Example XIV, except that lithium aluminum hydride was substituted by magnesium aluminum hydride, thus yielding a product identical with Compound No. 31.

Example XXXII The procedure described in Example XIV was repeated, except that zinc aluminum hydride was used instead of lithium aluminum hydride, thus giving exactly the same results.

Example XXXIZI Androstan-3,B-ol-l7-one was treated according to Example I, except that ethyleneglycol was substituted by cyclohexanol, thus yielding 17,17-di-(cyclohexyloxy)-3fihydroxy-androstane (Cpd. No. 73) which upon treatment according to Example XII, yielded l7B-(cyclohexyloxy)- 3/3-hydroxy-androstane (Cpd. No. 74).

Example XXXIV The Compound No. 1 was treated according to Example XII, except that lithium aluminum hydride was substituted by lithium hydride thus yielding a product identical with Compound No. 31.

Example XXX V The procedure of Example XIII was repeated, except that boron trifiuoride etherate and sodium hydride were respectively used instead of aluminum tribromide and sodium borohydride, thus furnishing exactly the same compound.

Example XXXVI The Compound No. 1 was treated according to Example XII, except that lithium aluminum hydride was substituted by magnesium hydride thus yielding a product identical with Compound No. 31.

I claim:

1. A process for production of a compound selected from the group consisting of steroidal ethers and thioethers which comprises treating the corresponding compound selected from the group consisting of ketals, monothioketals and dithioketals of ketones selected from the group consisting of the androstane, estrane, pregnane and 19-nor pregnane series and acetals, monothioacetals and dithioacetals of aldehydes selected from the group consisting of the a'ndrostane, estrane, pregnane and l9-norpregnane series with a reagent selected from the group consisting of a hydride of an element of subgroup III-A of the Periodic Chart, a hydride of an element of subgroup III-A of the Periodic Chart in the presence of a Lewis acid, an alkali metal hydride and an alkaline earth metal hydride each in the presence of a Lewis acid comprising an element of subgroup III-A of the Periodic Chart, a double metal hydride comprising at least one element of subgroup III-A of the Periodic Chart in the presence of a Lewis acid, a double metal hydride comprising at least one element of subgroup III-A of the Periodic Chart in the presence of a hydrogen halide and a hydride of an element of subgroup III-A of the Periodic Chart in the presence of a hydrogen halide.

2. The process of claim 1 wherein the reagent is lithium aluminum hydride in the presence of a Lewis acid.

3. The process of claim 1 wherein the reagent is sodium borohydride in the presence of a Lewis acid.

4. The process of claim 1 wherein the reagent is aluminum hydride in the presence of a Lewis acid.

5. The process of claim 1 wherein the reagent is di-' borane in the presence of a Lewis acid.

6. The process of claim 1 wherein the reagent is lithium aluminum hydride in the presence of a hydrogen halide.

7. The process of claim 1 wherein the reagent is sodium borohydride in the presence of a hydrogen halide.

8. The process of claim 1 wherein the reagent is aluminum hydride.

9. The process of claim 1 wherein the reagent is diborane.

it). The process of claim 1 wherein the reagent is lithium hydride in the presence of a Lewis acid comprising an element belonging to subgroup III-A of the Periodic Chart.

11. The process of claim 1 wherein the reagent is sodium hydride in the presence of a Lewis acid comprising an element belonging to subgroup III-A of the Periodic Chart.

12. The process of claim 1 wherein the reagent is mag nesium hydride in the presence of a Lewis acid comprising an element belonging to subgroup III-A of the Periodic Chart.

13. The process of claim 2 wherein the Lewis acid is aluminum trichloride.

14. The process of claim 3 wherein the Lewis acid is aluminum tribromide.

15. The process of claim 5 wherein the Lewis acid is boron trifluoride.

16. The process of claim 10 wherein the Lewis acid is aluminum trichloride.

17. The process of claim 11 wherein the Lewis acid is boron trifluoride.

18. The process of claim 12 wherein the Lewis acid is aluminum trichloride.

No references cited.

LEWIS GO'ITS, Primary Examiner. 

1. A PROCESS FOR PRODUCTION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDAL ETHERS AND THIOETHERS WHICH COMPRISES TREATING THE CORRESPONDING COMPOUND SELECTED FROM THE GROUP CONSISTING OF KETALS, MONOTHIOKETALS AND DITHIOKETALS OF KETONES SELECTED FROM THE GROUP CONSISTING OF THE ANDROSTANE, ESTRANE, PREGANE AND 19-NOR PREGANE SERIES AND ACETALS, MONOTHIOACETALS AND DITHIOACETALS OF ALDEHYDES SELECTED FROM THE GROUP CONSISTING OF THE ANDROSTANE, ESTRANE, PREGNANE AND 19-NORPREGNANE SERIES WITH A REAGENT SELECTED FROM THE GROUP CONSISTING OF A HYDRIDE OF AN ELEMENT OF SUBGROUP III-A OF THE PERIODIC CHART, A HYDRIDE OF AN ELEMENT OF SUBGROUP III-A OF THE PERIODIC CHART IN THE APRESENCE OF A LEWIS ACID, AN ALKALI METAL HYDRIDE AND AN ALKALINE EARTH METAL HYDRIDE EACH IN THE PRESENCE OF A LEWIS ACID COMPRISING AN ELEMENT OF SUBGROUP III-A OF THE PERIODIC CHART, A DOUBLE METAL HYDRIDE COMPRISING AT LEAST ONE ELEMENT OF SUBGROUP III-A OF THE PERIOD CHART IN THE PRESENCE OF A LEWIS ACID, A DOUBLE METAL HYDRIDE COMPRISING AT LEAST ONE ELEMENT OF SUBGROUP III-A OF THE PERIODIC CHART IN THE PRESENT OF A HYDROGEN HALIDE AND A HYDRIDE OF AN ELEMENT OF SUBGROUP III-A OF THE PERIODIC CHART IN THE PRESENCE OF A HYDROGEN HALIDE. 